LEC 1 PLATELETS OR THROMBOCYTES - for merge.pdf

PLATELETS OR THROMBOCYTES – trigger primary hemostasis on exposure to subendothelial collagen or endothelial cell inflammatory proteins at the time of blood vessel injury. Arise from unique bone marrow cells called MEGAKARYOCYTE.  Normal Platelets: nonnucleated blood cells | biconvex (resting) |...

PLATELETS OR THROMBOCYTES – trigger primary hemostasis on exposure to subendothelial collagen or endothelial cell inflammatory proteins at the time of blood vessel injury. Arise from unique bone marrow cells called MEGAKARYOCYTE.  Normal Platelets: nonnucleated blood cells | biconvex (resting) | average diameter: 2.5 µm | Mean Platelet Volume: 810 fL  Normal/average platelet count: 150-450 x 109/L (higher in women)| 2/3 in circulation | 1/3 sequestered in spleen  Reticulated/ Stress Platelets: Appear in compensation for thrombocytopenia | larger: > 6 µm | MPV: 12-14 fL  Arise from Megakaryocytes → largest cells in the BM | polypoid (multiple chromosome copies) | kidney (most abundant; primary source of TPO), stromal cells, smooth muscle circulates as a hormone in plasma - Receptor: MPL (myeloproliferative leukemia viral oncogene) - ↑ plasma concentration of TPO = ↓ platelet and megakaryocyte mass BOOK NOTES: - The growth factor TPO is a 70,000 Dalton molecule that possesses 23% homology with the red blood cell-producing hormone erythropoietin. Messenger ribonucleic acid (mRNA) for TPO has been found in the kidney, liver, stromal cells, and smooth muscle cells, though the liver has the most copies and is considered the primary source. TPO circulates as a hormone in plasma and is the ligand that binds the megakaryocyte and platelet membrane receptor protein identified earlier, MPL, named for v-mpl, a viral oncogene associated with murine myeloproliferative leukemia. The plasma concentration of TPO is inversely proportional to platelet and megakaryocyte mass, implying that membrane binding and consequent removal of TPO by platelets is the primary platelet count control mechanism. Synthetic TPO analogs: (effective in increasing the platelet production) - Romiplostim (MPL receptor agonist) ex. ITP (Immune thrombocytopenic purpura) - Eltrombopag (MPL receptor agonist) – exogenously manufactuted BOOK NOTES: Synthetic TPO mimetics (analogs) elevate the platelet count in patients being treated for a variety of cancers, including acute leukemia. One commercial TPO mimetic, romiplostim (NPlate, Amgen), is a nonimmunogenic oligopeptide that is effective in raising the platelet count in patients with chronic immune thrombocytopenic purpura (ITP).16 A second nonpeptide TPO mimetic, eltrombopag (Promacta, Novartis), binds an MPL site separate from romiplostim and is used in the treatment of chronic ITP and in patients with thrombocytopenia resulting from chronic hepatitis C or severe aplastic anemia. They may have additive effects. Roles: 1. Induces differentiation of stem cells into megakaryocyte progenitors 2. Induces differentiation of megakaryocyte progenitors into precursor cells and ultimately, megakaryocytes 3. Induces proliferation and maturation of megakaryocytes 4. Induces thrombocytopoiesis BOOK NOTES: Investigators have used both in vitro and in vivo experiments to show that TPO, in synergy with other cytokines, induces stem cells to differentiate into megakaryocyte progenitors and that it further induces the differentiation of megakaryocyte progenitors into megakaryoblasts and megakaryocytes. TPO also induces the proliferation and maturation of megakaryocytes and induces thrombocytopoiesis. 2. IL-3 - acts in synergy with TPO; induces early differentiation of stem cells 3. IL-6 and IL-11 - act in the presence of TPO; enhance endomitosis, megakaryocyte maturation and thrombocytopoiesis - synthetic IL-11 analogs: oprelvekin (increase platelet) – drug for chemotherapy patient to induced thrombocytopenia. BOOK NOTES: Other cytokines that function with TPO to stimulate megakaryocytopoiesis include interleukin-3 (IL-3), IL-6, and IL-11. IL-3 seems to act in synergy with TPO to induce the early differentiation of stem cells, whereas IL-6 and IL-11 act in the presence of TPO to enhance endomitosis, megakaryocyte maturation, and thrombocytopoiesis. An IL-11 polypeptide mimetic, oprelvekin (Neumega, Pfizer), stimulates platelet production in patients with chemotherapy-induced thrombocytopenia. Other cytokines that work synergistically with TPO:  KIT ligand/stem cell factor/mast cell growth factor  GM-CSF (granulocyte-macrophage colony-stimulating factor)  G-CSF ( granulocyte- colony stimulating factor)  acetylcholinesterase-derived megakaryocyte growth stimulating peptide BOOK NOTES: Other cytokines and hormones that participate synergistically with TPO and the interleukins are stem cell factor, also called kit ligand or mast cell growth factor; granulocyte-macrophage colony stimulating factor (GM-CSF); granulocyte colony-stimulating factor (G-CSF); and acetylcholinesterase-derived megakaryocyte growth stimulating peptide. Platelet factor 4 (PF4), b-thromboglobulin, neutrophil activating peptide 2, IL-8, and other factors inhibit in vitro megakaryocyte growth, which indicates that they may have a role in the control of megakaryocytopoiesis in vivo. Internally, reduction in the transcription factors FOG1, GATA-1, and NF-E2 diminish megakaryocytopoiesis at the progenitor, endomitotic, and terminal maturation phases. Factors that inhibit in vitro megakaryocyte growth:  Platelet Factor 4 (PF4)  β-thromboglobulin  Neutrophil-activating peptide 2  IL-8 GATA-1, FOG1, NF-E2 (influence in all stages in maturation megakaryocytes) - stimulates megakaryocyte differentiation MYB - transcription gene product which suppresses megakaryocyte differentiation *Notes: Being used: decrease level of TPO in the plasma or serum Not used: stay in circulation (normal) – increased level of TPO , decrease platelets The more TPO bind in the receptor, the more platelets being produce = reason: body is needing \